A fine-tuned lipophilicity/hydrophilicity ratio governs antibacterial potency and selectivity of bifurcated halogen bond-forming NBTIs

Kolarič, Anja (avtor), Kokot, Maja (avtor), Hrast, Martina (avtor), Weiss, Matjaž (avtor), Zdovc, Irena (avtor), Trontelj, Jurij (avtor), Žakelj, Simon (avtor), Anderluh, Marko (avtor), Minovski, Nikola (avtor)

Herein, we report the design of a focused library of novel bacterial topoisomerase inhibitors (NBTIs) based on innovative mainly monocyclic right-hand side fragments active against DNA gyrase and Topo IV. They exhibit a very potent and wide range of antibacterial activity, even against some of the most concerning hard-to-treat pathogens for which new antibacterials are urgently needed, as reported by the WHO and CDC. NBTIs enzyme activity and whole cell potency seems to depend on the fine-tuned lipophilicity/hydrophilicity ratio that governs the permeability of those compounds through the bacterial membranes. Lipophilicity of NBTIs is apparently optimal for passing through the membrane of Gram-positive bacteria, but the higher, although not excessive lipophilicity and suitable hydrophilicity seems to determine the passage through Gram-negative bacterial membranes. However, due to the considerable hERG inhibition, which is still at least two orders of magnitude away from MICs, continued optimization is required to realize their full potential.

• Jezik: Angleški jezik
• Ključne besede: antibacterials, drug discovery, DNA gyrase inhibitors, topoisomerase IV inhibitors, intercalators, novel bacterial topoisomerase inhibitors, topoisomerase II inhibitors, intercalating agents
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo ; VF - Veterinarska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2021
• Št. strani: 30 str.
• Številčenje: Vol. 10, iss. 7, art. 862
• PID: 20.500.12556/RUL-135734
• UDK: 615.4:54
• ISSN pri članku: 2079-6382
• DOI: 10.3390/antibiotics10070862
• COBISS.SI-ID: 70416899
• Datum objave v RUL: 30.03.2022

Gradivo je del revije

• Naslov: Antibiotics
• Skrajšan naslov: Antibiotics
• Založnik: MDPI
• ISSN: 2079-6382
• COBISS.SI-ID: 522975769

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 15.07.2021

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: farmacevtska kemija, antibakterijska sredstva, raziskave zdravil, zaviralci DNA giraz, zaviralci topoizomeraze IV, interkalator, novi zaviralci bakterijske topoizomeraze

Projekti

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: P1-0017
• Naslov: Modeliranje kemijskih procesov in lastnosti spojin

• Financer: ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
• Številka projekta: P1-0208
• Naslov: Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin